NEGR1 and FGFR2 cooperatively regulate cortical development and core behaviours related to autism disorders in mice.
Brain
; 141(9): 2772-2794, 2018 09 01.
Article
en En
| MEDLINE
| ID: mdl-30059965
ABSTRACT
Autism spectrum disorders are neurodevelopmental conditions with diverse aetiologies, all characterized by common core symptoms such as impaired social skills and communication, as well as repetitive behaviour. Cell adhesion molecules, receptor tyrosine kinases and associated downstream signalling have been strongly implicated in both neurodevelopment and autism spectrum disorders. We found that downregulation of the cell adhesion molecule NEGR1 or the receptor tyrosine kinase fibroblast growth factor receptor 2 (FGFR2) similarly affects neuronal migration and spine density during mouse cortical development in vivo and results in impaired core behaviours related to autism spectrum disorders. Mechanistically, NEGR1 physically interacts with FGFR2 and modulates FGFR2-dependent extracellular signal-regulated kinase (ERK) and protein kinase B (AKT) signalling by decreasing FGFR2 degradation from the plasma membrane. Accordingly, FGFR2 overexpression rescues all defects due to Negr1 knockdown in vivo. Negr1 knockout mice present phenotypes similar to Negr1-downregulated animals. These data indicate that NEGR1 and FGFR2 cooperatively regulate cortical development and suggest a role for defective NEGR1-FGFR2 complex and convergent downstream ERK and AKT signalling in autism spectrum disorders.
Texto completo:
1
Base de datos:
MEDLINE
Asunto principal:
Moléculas de Adhesión Celular Neuronal
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Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos
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Trastorno del Espectro Autista
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Brain
Año:
2018
Tipo del documento:
Article